ATRX histone binding and helicase activities have distinct roles in neuronal differentiation
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ABSTRACT:
PROVIDER: PRJNA798392 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17654800_1.fastq.gz | Fastqsanger.gz | |||
| SRR17654800_2.fastq.gz | Fastqsanger.gz | |||
| SRR17654801_1.fastq.gz | Fastqsanger.gz | |||
| SRR17654801_2.fastq.gz | Fastqsanger.gz | |||
| SRR17654802_1.fastq.gz | Fastqsanger.gz |
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Project description:We have identified the distinct effects on neuronal differentiation of two different mutations of ATRX. We generated E14 mouse embryonic stem cell lines with mutations in the histone binding domain of ATRX (PHDmut) or in the helicase domain (K1584R). Neurodifferentiation is both delayed and compromised in PHDmut and K1584R, and manifest differently from complete ATRX loss. We performed ATRX ChIP-seq which showed changes in occupancy of ATRX in PHDmut and K1584R. Our CUT&RUN and RNA-Seq reveal that mutations or deficiency of ATRX result in separate patterns of dysregulation in gene expression and PRC2 binding, suggesting different roles of each ATRX domain in neuronal differentiation
2022-09-01 | GSE193910 | GEO
Project description:ATRX is a chromatin remodeler, which is mutated in ATRX syndrome, a neurodevelopmental disorder. ATRX mutations that alter histone binding or chromatin remodeling activities cluster in the PHD finger or the helicase domain respectively. Using engineered mouse embryonic stem cells that exclusively express ATRX protein with mutations in the PHD finger (PHDmut) or helicase domains (K1584R), we examine how specific ATRX mutations affect neurodifferentiation. ATRX PHDmut and K1584R proteins interact with the DAXX histone chaperone but show reduced localization to pericentromeres. Neurodifferentiation is both delayed and compromised in PHDmut and K1584R, and manifest differently from complete ATRX loss. We observe reduced enrichment of PHDmut protein to ATRX targets, while K1584R accumulates at these sites. Interestingly, ATRX mutations have distinct effects on the genome-wide localization of the polycomb repressive complex 2 (PRC2), with PHDmut and ATRX knockout showing reduced PRC2 binding at polycomb targets and K1584R showing loss at some sites and gains at others. Notably, each mutation associated with unique gene signatures, suggesting distinct pathways leading to impaired neurodifferentiation. Our results indicate that the histone binding and chromatin remodeling functions of ATRX play non-redundant roles in neurodevelopment, and when mutated lead to ATRX syndrome through separate regulatory pathways.
| S-EPMC9458459 | biostudies-literature
Project description:Purpose: the chromatin-remodeler ATRX is frequently mutated in a range of human malignancies including pediatric and adult gliomas, and its loss underlies induction of alternative lengthening of telomeres (ALT) pathway for chromosome-end maintenance. But how ATRX exters its glioma suppresor role remains unclear. Here, we combine RNAi and somatic deletion approaches to demonstrate ATRX as a glioma suppressor controlling neural differentiation. Loss of ATRX promotes gliomagenesis by blocking neuronal progenitors from undergoing terminal maturation. Our findings provide the molecular and cellular mechanism underline ATRX's function in gliomagenesis.
2015-10-01 | GSE73447 | GEO
Project description:Heterochromatin in the eukaryotic genome is rigorously controlled by the concerted action of protein factors and RNAs. Here, we investigate the RNA binding function of ATRX, a chromatin remodeler with roles in silencing of repetitive regions of the genome and in recruitment of the polycomb repressive complex 2 (PRC2). We identify ATRX RNA binding regions (RBRs) and discover that the major ATRX RBR lies within the N-terminal region of the protein, distinct from its PHD and helicase domains. Deletion of this ATRX RBR (ATRXRBR) compromises ATRX interactions with RNAs in vitro and in vivo and alters its chromatin binding properties. Genome-wide studies reveal that loss of RNA interactions results in a redistribution of ATRX on chromatin. Finally, our studies identify a role for ATRX-RNA interactions in regulating PRC2 localization to a subset of polycomb target genes.
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Project description:We report on the characterization of ATRX in-frame fusion neuroblastoma and identify that ATRX IFF proteins re-locate from H3K9me3 enriched regions to active chromatin, such as the promoter of neural repressor REST. We further identify that REST is upregulated in ATRX IFF NB and that several neurogenesis and REST target genes are transcriptionally downregulated. Through ChIP-seq analysis, we observe that REST is bound to ATRX IFF Down genes, which have higher levels of H3K27me3. We further show that ATRX in-frame fusion neuroblastoma cells are sensitive to EZH2 inhibitors through de-repression of H3K27me3 bound neuronal function genes, includiing a subset of REST targets.
2019-10-15 | GSE100148 | GEO
Project description:The histone variant macroH2A generally associates with transcriptionally inert chromatin, however the factors that regulate its chromatin incorporation remain elusive. Here, we identify the SWI/SNF helicase, ATRX, as a novel macroH2A interacting protein. Unlike its role in assisting H3.3 chromatin deposition, ATRX acts as a negative regulator of macroH2A’s chromatin association. In human erythroleukemic cells deficient for ATRX, ChIP-sequencing studies reveal that macroH2A accumulates at the HBA gene cluster on the subtelomere of chromosome 16, coinciding with the loss of α globin expression. Collectively, our results implicate deregulation of macroH2A’s distribution as a contributing factor to the α thalassemia phenotype of ATRX syndrome. Mononucleosomes from K562 cells bearing integrated lentiviral shRNA constructs targeting either luciferase (shluc) or ATRX (sh92) were isolated and ChIP'd with mH2A1 antibody. DNA from shluc Input and the two mH2A1 ChIPs were isolated and sequenced on Illumina's Hiseq.
2012-03-08 | E-GEOD-35339 | biostudies-arrayexpress
Project description:ATRX is a severe X-linked disorder characterized by mental retardation, facial dysmorphism, urogenital abnormalities and alpha-thalassemia. The disease is caused by mutations in ATRX gene, which encodes a protein belonging to the SWI/SNF DNA helicase family, a group of proteins involved in the regulation of gene transcription at the chromatin level. In order to identify specific genes involved in the pathogenesis of the disease, we compared, by cDNA microarray, the expression levels of approximately 8500 transcripts between ATRX and normal males of comparable age. The analysis has been performed on pooled RNA extracted by Peripheral blood mononuclear cell pellet of three male ATRX patients in comparison to that obtained from a pool of 42 normal males (age 7.6+ 2.4).
2010-12-31 | E-GEOD-22028 | biostudies-arrayexpress
Project description:Through an integration of genomic and proteomic approaches to advance understanding of long noncoding RNAs, we investigate the function of the telomeric transcript, TERRA. By identifying thousands of TERRA target sites in the mouse genome, we demonstrate that TERRA can bind both in cis to telomeres and in trans to genic targets. We then define a large network of interacting proteins, including epigenetic factors, telomeric proteins, and the RNA helicase, ATRX. TERRA and ATRX share hundreds of target genes and are functionally antagonistic at these loci: whereas TERRA activates, ATRX represses gene expression. At telomeres, TERRA competes with telomeric DNA for ATRX binding, suppresses ATRX localization, and ensures telomeric stability. Depleting TERRA increases telomerase activity and induces telomeric pathologies, including formation of telomere-induced DNA damage foci and loss or duplication of telomeric sequences. We conclude that TERRA functions as an epigenomic modulator in trans and as an essential regulator of telomeres in cis.
2017-06-29 | GSE79180 | GEO
Project description:The histone variant macroH2A generally associates with transcriptionally inert chromatin, however the factors that regulate its chromatin incorporation remain elusive. Here, we identify the SWI/SNF helicase, ATRX, as a novel macroH2A interacting protein. Unlike its role in assisting H3.3 chromatin deposition, ATRX acts as a negative regulator of macroH2A’s chromatin association. In human erythroleukemic cells deficient for ATRX, ChIP-sequencing studies reveal that macroH2A accumulates at the HBA gene cluster on the subtelomere of chromosome 16, coinciding with the loss of α globin expression. Collectively, our results implicate deregulation of macroH2A’s distribution as a contributing factor to the α thalassemia phenotype of ATRX syndrome.
2012-03-08 | GSE35339 | GEO
Project description:Heterochromatin Protein 1 (HP1) is a major regulator of chromatin structure and function. In animals, the network of proteins interacting with HP1 is mainly associated with constitutive heterochromatin marked by H3K9me3. HP1 physically interacts with the putative orthologue of the SNF2 chromatin remodeler ATRX, which controls deposition of the histone variant H3.3 in mammals. In Arabidopsis thaliana, we show that the orthologue of ATRX participates in H3.3 deposition and characterize the function of conserved domains of plant ATRX. We show that the plant Like HP1 (LHP1) interacts with ATRX through domains that evolved specifically in land plants ancestors. Interaction between ATRX and LHP1 affects the expression of a limited subset of genes controlled by the POLYCOMB REPRESSIVE COMPLEX 2 (PRC2), including the flowering time regulator FLC. In the context of flowering time, ATRX function requires the novel LHP1-interacting domain and the ATPase of the ATRX SNF2 helicase. We conclude that distinct evolutionary pathways led to interaction between ATRX and HP1 in mammals or its counterpart LHP1 in plants, resulting in distinct modes of transcriptional regulation.
2018-06-26 | GSE101777 | GEO